Empowering Fertility - Hyperemesis Gravidarum: Update on Treatment Options   
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Hyperemesis Gravidarum: Update on Treatment Options   

By Paul Bergh, MD

Hyperemesis gravidarum (HG) is a miserable disease with serious short and long term consequences for both mother and baby. It deserves our serious attention so that timely medical and psychosocial resources can be brought to bear at an early stage.  It is a severe manifestation of the common and what some consider normal nausea and vomiting of pregnancy (NVP).  The treatment options range from diet to medications to the extreme of pregnancy termination.

Treatment for any patient should always be directed toward reducing symptoms while posing the least amount of risk to the fetus and mother.

Non Pharmacologic:

Diet and Lifestyle:

Despite the lack of  good evidence to support dietary recommendations, many women report benefit from some of the following recommendations:

  • Since mixing solids and liquids, can increase nausea, eating dry crackers before getting out of bed and small frequent portions every 1 to 2 hours. Waiting 20 to 30 minutes after eating to take some fluids may be helpful.
  • High protein meals,  lean meat, fruits, vegetables, peanut butter, crackers, eggs, and tofu are commonly recommended foods and may be beneficial
  • Spicy, fatty, foods with strong smells and fried foods should be avoided
  • Fluid intake in pregnancy requires a minimum of 2 liters of fluids daily, best taken in small, frequent amounts throughout the day. Cold fluids including ice chips and popsicles may be easier to tolerate.  Commercial electrolyte balanced sports drinks may also be better tolerated.
  • Large prenatal vitamins especially with iron may worsen nausea though there is some evidence that women who are taking prenatal vitamins prior to pregnancy may have reduced severity of symptoms.  Chewable prenatal vitamins with reduced iron or folic acid alone can be substituted if necessary for the first trimester with resumption of normal prenatal vitamins later in pregnancy.
  • Women with symptoms of excess saliva production (ptyalism) should be advised spit excess saliva as swallowing may exacerbate her symptoms.

Acupuncture / Acupressure:

There is mixed data supporting the use of either acupressure or acupuncture to relieve symptoms of NVP.  Acupressure can be performed manually or obtained with the use of wristbands.  Studies evaluating acupuncture have been limited to traditional methods with insertion of needles into the skin.

Herbal:

A commonly used “natural” remedy is ginger root, a herbaceous perennial.  Ginger is available raw or in many other forms including capsules, crystals, and extracts. It can an additive in may products including teas, sodas, baked goods, and candies.  The hypothesized physiological mechanism by which ginger affects the digestive system includes its ability to enhance gastric contractility, speeding up gastric emptying, and thus decreasing the feeling of nausea. There are numerous studies, including several small randomized trials demonstrating the efficacy of ginger 250mg  capsules 4 x daily for the treatment of NVP.  Most of these studies provided 1000 mg of ginger powder or capsules for a period of 4 days to women suffering from NVP.  There were no reported side-effects or adverse events with this regime. This literature recommends taking the total dose in three to four divided doses during the day, irrespective of mealtimes.

Symptomatic pregnant women can also be advised to use ginger freely in their cooking, to drink ginger tea and soda, and to have dry ginger biscuits or candy as needed. While data is limited, evidence to date is very reassuring, and it is generally considered safe to take ginger in pregnancy.

Intravenous Fluids and Electrolytes

It is not uncommon for women with HG to suffer from dehydration due to severe vomiting.  Intermittent intravenous (IV) hydration can be very effective in preventing dehydration and delivery needed vitamin supplements. One or two liters of normal saline are often enough to improve symptoms. In the most severe cases, parental nutrition may be required.  As this bypasses the gastrointestinal tract, it typically does not contribute to patients symptoms of nausea and vomiting

Pharmacologic

Background:

In 2013, for the first time in 30 years, the US Food and Drug Administration (FDA) approved a new medication, named Diclegis®  (pronounced:dye-CLEE-gis), for the treatment of nausea and vomiting in pregnancy.  It is not a new product as it is just a version of the medication Bendectin®, which was originally manufactured by Merrill Dow.  While Bendectin had an excellent safety record supported by reams of data,  it was voluntarily removed from the market by the manufacturer in the early 1980s because of costs associated with the defense of malpractice litigation. The baseline risk of congenital abnormalities in the general population is not insignificant at 3%.   Since the majority of pregnant women will experience NPV, it is no surprise that in the 1970’s 30% to 35% of pregnant women were taking Bendectin during pregnancy. Thus, 30% to 35% of children born with a congenital anomaly were exposed to this medication, making it an attractive target for litigation.  An example of such a litigation was brought by Mekdeci in the 1980s.  The Mekdeci plaintiff had Poland syndrome, which is believed to be caused an interruption of the embryonic blood supply to the arteries that lie under the collar bone (subclavian arteries) at about the 46th day of embryonic development. The case was tried twice: In the first trial, the jury found that Bendectin did not cause the malformations; however, they awarded $20,000 to the family. The jury’s rationale was that they wanted to compensate the family.  The judge reversed this decision. In the second trial, the jury also rendered a verdict in favor of the manufacturer.  Though virtually all of these suites were not justified and ultimately won by manufacturer, the manufacturer’s insurance premiums exceeded the gross sales for Bendectin, and thus they pulled it from the market.  The unavailability of Bendectin then led to a two-fold increase in hospital admissions  for severe NVP in the US.  This unfortunate turn of events was described by the International Federation of Gynecology and Obstetrics (FIGO) as “the worst example in history of women being denied medication without a cause.”

The equivalent drug to Bendectin in Canada is labeled Diclectin and has been on the market for many years.

Primary Therapy 

Diclegis consists of a combination of two medications,  doxylamine succinate 10 mg and pyridoxine hydrochloride 10 mg. Doxylamine succinate is an antihistamine  and can be found in popular over the counter (OTC) cold remedies and sleeping aids (Nyquil®, Unisom®).  Pyridoxine hydrochloride is a form of Vitamin B6.  While the mechanism of action is not clear, the combination of doxylamine and  pyridoxine has been shown to be effective over  placebo in clinical trials (Koren et al., 2010).  The initial starting dose is two tablets at bedtime.  If symptoms still persist on the third day of treatment, the dose can be increased to one tablet in the morning and two tablets at bedtime.  If still no relief, the final, maximum dose of one tablet in the morning, one in mid-afternoon and two at bedtime can be implemented the following day (day 4 of treatment).

The most recent American College of Obstetricians and Gynecologists (ACOG) guidelines for nausea and vomiting of pregnancy were published in 2004.  At this time, Bendectin was no longer available, and Diclegis was yet to be introduced. These guidelines recommend first-line pharmacologic  treatment  as vitamin B6 monotherapy (10-25 mg, 3-4 times per day).  In the event symptoms do not improve; the addition of doxylamine (12.5 mg, 3-4 times per day; half a tablet of Unisom SleepTabs) is recommended.  Given the cost of Diclegis, this may be a more acceptable route of treatment for many patients.

Secondary Therapy

In the event of a lack of response, promethazine (Phenergan®) 12.5mg to 25 mg  orally or rectally every 4 hours as needed  can be added to a patient’s treatment regime.  An alternative to this would be the addition of dimenhydrinate (Dramamine®) 50mg to 100mg every 4 to 6 hours orally or rectally, not to exceed  400mg per day  or 200mg per day if patient is also taking doxylamine.

If no results, next steps include any of the following:

If no dehydration present:

Metoclopramide (Reglan®) 5mg to 10mg every 8 hours orally (po) or intramuscularly (IM)

Promethazine (Phenergan®) 12.5mg to 25mg every 4 hours po, IM, or rectally

Trimethobenzamide (Tigan®) 200mg every 6 to 8 hours rectally

Ondansetron (Zofran®) 4 to 8mg every 6 to 8 hours po

If dehydration present:

IV fluid replacement  plus:

Dimenhydrinate (Dramamine®) 50mg in 50ml of saline IV infusion over 20 min every 4 to 6 hours

Metoclopramide (Reglan®) 5mg to 10mg every 8 hours IV

Promethazine (Phenergan®) 12.5mg to 25mg every 4 hours IV

If no results with above treatment

Ondansetron (Zofran®) 8mg over 15 min every 12 hours IV

Therapy for Refractory HG

In the most refractory situations of HG, patients may make the heartbreaking choice to terminate the pregnancy.  For many of these patients, the fear of pregnancy leads them to pursue any future pregnancy with in-vitro fertilization and the use of a gestational carrier.

Psychosocial support:

Hyperemesis gravidarum is an extremely distressing and debilitating disease for both the patient and her family.  An  in-depth analysis of women with this condition by Power et al suggests that the professional care-giver’s attitude and support or lack of it can dramatically affect a women’s experience and access to appropriate treatment for this condition.  Many women with HG felt unsupported and voiced an awareness of their unpopularity with the professional staff as patients.  They felt as they were perceived as not truly ill, as “time-wasters”, or as someone else’s problem. These perceptions not only compounded a difficult physical and psychological situation, but such attitudes lead to a delay or absence of treatment.  Given the serious short and long-term consequences of this condition, it is imperative that  health care providers avail these patients their full, compassionate attention and resources.

References:

Chandra, K., Magee, L., Einarson, A., and Koren, G. Nausea and vomiting in pregnancy: results of a survey that identified interventions used by women to alleviate their symptoms. J.Psychosom.Obstet.Gynaecol. 24(2), 71-75. 2003

Einarson, A., Maltepe, C., Boskovic, R., and Koren, G. Treatment of nausea and vomiting in pregnancy: an updated algorithm. Can.Fam.Physician 53(12), 2109-2111. 2007

Nguyen, P. and Einarson, A. Managing nausea and vomiting of pregnancy with pharmacological and nonpharmacological treatments. Womens Health (Lond Engl.) 2(5), 753-760. 2006

Castillo, M. J. and Phillippi, J. C. Hyperemesis gravidarum: a holistic overview and approach to clinical assessment and management. J Perinat.Neonatal Nurs. 29(1), E1. 2015.

Festin, M. Nausea and vomiting in early pregnancy. Clin Evid.(Online.) 2014. 2014.

King, T. L. and Murphy, P. A. Evidence-based approaches to managing nausea and vomiting in early pregnancy. J Midwifery Womens Health 54(6), 430-444. 2009.

Matthews, A., Haas, D. M., O’Mathuna, D. P., Dowswell, T., and Doyle, M. Interventions for nausea and vomiting in early pregnancy. Cochrane.Database.Syst.Rev. 3, CD007575. 2014.

Chandra, K., Einarson, A., and Koren, G. Taking ginger for nausea and vomiting during pregnancy. Can.Fam.Physician 48, 1441-1442. 2002.

Portnoi, G., Chng, L. A., Karimi-Tabesh, L., Koren, G., Tan, M. P., and Einarson, A. Prospective comparative study of the safety and effectiveness of ginger for the treatment of nausea and vomiting in pregnancy. Am.J.Obstet.Gynecol. 189(5), 1374-1377. 2003.

Viljoen, Estelle, Visser, Janicke, Koen, Nelene, and Musekiwa, Alfred. A systematic review and meta-analysis of the effect and safety of ginger in the treatment of pregnancy-associated nausea and vomiting. Nutrition Journal 13, 20. 3-19-2014.

Ismail, S. K. and Kenny, L. Review on hyperemesis gravidarum. Best.Pract.Res.Clin.Gastroenterol. 21(5), 755-769. 2007.

Goodwin, T. M., Poursharif, B., Korst, L. M., MacGibbon, K. W., Romero, R., and Fejzo, M. S. Secular trends in the treatment of hyperemesis gravidarum. Am.J.Perinatol. 25(3), 141-147. 2008.

Brent, R. Medical, social, and legal implications of treating nausea and vomiting of pregnancy. Am.J.Obstet.Gynecol. 186(5 Suppl Understanding), S262-S266. 2002.

Miller, F. Nausea and vomiting in pregnancy: the problem of perception–is it really a disease? Am.J.Obstet.Gynecol. 186(5 Suppl Understanding), S182-S183. 2002.

Herrell, H. E. Nausea and vomiting of pregnancy. Am.Fam.Physician 89(12), 965-970. 6-15-2014

Fantasia, H. C. A new pharmacologic treatment for nausea and vomiting of pregnancy. Nurs.Womens Health 18(1), 73-77. 2014.

Arsenault, M. Y., Lane, C. A., MacKinnon, C. J., Bartellas, E., Cargill, Y. M., Klein, M. C., Martel, M. J., Sprague, A. E., and Wilson, A. K. The management of nausea and vomiting of pregnancy. J Obstet.Gynaecol.Can. 24(10), 817-831. 2002.

ACOG (American College of Obstetrics and Gynecology) Practice Bulletin: nausea and vomiting of pregnancy. Obstet.Gynecol. 103(4), 803-814. 2004.

Koren, G., Clark, S., Hankins, G. D., Caritis, S. N., Miodovnik, M., Umans, J. G., and Mattison, D. R. Effectiveness of delayed-release doxylamine and pyridoxine for nausea and vomiting of pregnancy: a randomized placebo controlled trial. Am.J.Obstet.Gynecol. 203(6), 571-577. 2010.

Oliveira, L. G., Capp, S. M., You, W. B., Riffenburgh, R. H., and Carstairs, S. D. Ondansetron compared with doxylamine and pyridoxine for treatment of nausea in pregnancy: a randomized controlled trial. Obstet.Gynecol. 124(4), 735-742. 2014.

Empowering Fertility: An educational blog for patients & healthcare professionals that empowers individuals to take charge of their fertility. Visit us at http://empoweringfertility.com.

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